A method for synthesizing gefaryl esters from farnesene and its derivatives and its application

Abstract

A method for synthesizing gefarin esters from farnesene and its derivatives, and their applications. This invention belongs to the field of gefarin ester synthesis. The purpose of this invention is to solve the technical problems of existing gefarin ester synthesis methods, such as long routes, numerous side reactions, high toxicity and irritation of reagents, and low yields. This invention uses farnesene as a starting material, reacting it with acetoacetate in the presence of a catalyst to obtain farnesene ketoester, which is then decarboxylated to generate farnesene acetone. Following haloform reaction and esterification, gefarin esters are obtained. The method of this invention has fewer conversion steps and a high yield of gefarin esters. The gefarin esters of this invention are used as a drug for treating gastric diseases.

Description

Technical Field

[0001] This invention belongs to the field of gefarin synthesis, specifically relating to a method for synthesizing gefarin from farnesene and its derivatives and its application. Background Technology

[0002] Gefaryl acetate can act on gastric mucosal epithelial cells, enhance their anti-ulcer factors, regulate gastrointestinal function and gastric acid secretion, and strengthen mucosal protection, thereby playing a role in the prevention and treatment of gastric and duodenal ulcers, acute and chronic gastritis, colitis, and gastric spasm.

[0003] The reported synthetic routes for gefaryl esters are mainly as follows: (1) In patent CN101973879, farnesyl acetate is first chlorinated and then reacted with geraniol to generate gefaryl ester. This method requires the use of acyl chloride reagents such as thionyl chloride and phosphorus oxychloride, which are highly irritating and toxic, and are not environmentally friendly. (2) In patent CN102146039A, triphenylphosphine, diisopropyl azodicarbonate (DIPA), farnesyl acetate, and geraniol are reacted to generate gefaryl ester. The disadvantage of this method is that it requires a large number of reagents, has a high cost, and requires high control of reaction conditions. In addition, triphenylphosphine is highly toxic. (3) In patent CN201110267137, nerolidol is used as a substrate to synthesize farnesyl acetate through halogenation, decarboxylation, and other pathways. However, this process has a long reaction time and a low overall yield. (4) Patent CN103012140A describes the synthesis of farneseth ethyl acetate via a Witting reaction using geraniol and phosphorus ylide reagent as substrates. This is followed by hydrolysis to produce farneseth acetic acid, which is then reacted with geraniol in the presence of polymerization inhibitors (such as phenol, hydroquinone, or nitrophenol) using xylene as a solvent to synthesize gefaryl ester. This method involves high reaction temperatures, numerous byproducts, and high energy consumption for industrial production. Furthermore, the toxicity and hazard of xylene increase with increasing temperature. Therefore, there is an urgent need to develop a low-cost, simplified industrial production process. Summary of the Invention

[0004] The purpose of this invention is to solve the technical problems of existing methods for synthesizing gefarin, such as long routes, numerous side reactions, high toxicity and irritation of reagents, and low yield. This invention provides a method for synthesizing gefarin from farnesene and its derivatives, and its application.

[0005] One objective of this invention is to provide a method for synthesizing gefaryl esters from farnesene and its derivatives, the method comprising the following steps:

[0006] Step 1: First, farnesene and acetoacetate are synthesized into farnesene ketoester under the action of a catalyst, and then decarboxylated by hydrolysis under the action of an alkaline catalyst to obtain farnesene acetone;

[0007] Step 2: Farnesyl acetone was subjected to a haloform reaction using a halogenating agent to obtain sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate.

[0008] Step 3: Under the action of a catalyst, the product of Step 2 is subjected to an esterification reaction using an esterification reagent to obtain gefaryl ester.

[0009] Further specifying, in step 1, farnesene is one or a mixture of two of β-farnesene and α-farnesene in any ratio.

[0010] Further specifying, the acetoacetate in step 1 includes methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isobutyl propyl acetoacetate, and tert-butyl acetoacetate.

[0011] Further specifying, the catalyst in step 1 is a rhodium-containing compound.

[0012] To be further specified, rhodium-containing compounds include (acetylacetone) dicarbonyl rhodium.

[0013] Further specifying, the alkaline catalyst in step 1 includes aqueous solutions of sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, lithium chloride, lithium bromide, and lithium iodide.

[0014] Further specifying, in step 1, the mass ratio of farnesene to acetoacetate and catalyst is (70-90):(50-70):1.

[0015] Further specifying, in step 1, the mass ratio of farnesene ketone ester to the dry weight of the alkaline catalyst is (900-1000):1.

[0016] Further specifying, the halogenating reagent in step 2 includes a mixture of elemental iodine and sodium hydroxide solution, and sodium hypochlorite solution.

[0017] Furthermore, when the halogenating reagent is a mixture of elemental iodine and sodium hydroxide solution, the mass ratio of elemental iodine, sodium hydroxide and farnesyl acetone is (2-5):(0.5-2):1; when the halogenating reagent is sodium hypochlorite solution, the mass ratio of sodium hypochlorite and farnesyl acetone is (0.5-2.5):1.

[0018] Further specifying, the haloform reaction temperature in step 2 is 20-70℃.

[0019] Further specifying, the esterification reagent in step 3 includes 1-bromo-3,7-dimethyl-2,6-octadiene.

[0020] Further specifying, the catalyst in step 3 is sodium p-toluenesulfonate.

[0021] Further specifying, in step 3, the mass ratio of the product from step 2, the esterification reagent, and the catalyst is (15-25):(10-20):1.

[0022] Further specifying, the esterification reaction temperature in step 3 is 50-140℃.

[0023] The second objective of this invention is to provide a gefa ester prepared by the above method.

[0024] A third objective of this invention is to provide a gefaryl ester prepared by the above method for use as a drug for treating gastric diseases.

[0025] To further define, stomach diseases include acute gastritis, chronic gastritis, gastric ulcers, and gastric mucosal lesions.

[0026] The significant advantages of this invention compared to existing technologies are:

[0027] 1) This invention uses farnesene as a starting material, which reacts with acetoacetate under the action of a catalyst to obtain farnesene ketoester, which is then decarboxylated to generate farnesene propionate. After haloform reaction, esterification and other steps, gefa ester is obtained. The method of this invention has fewer conversion steps in the synthetic route and a high yield of gefa ester.

[0028] 2) The synthesis method of the present invention uses readily available raw materials and easily separated intermediates, which can reduce product loss caused by traditional separation processes, resulting in higher purity and yield of the overall reaction process. Attached Figure Description

[0029] Figure 1 This is a synthetic route diagram of the gefarin of the present invention;

[0030] Figure 2 The 1H NMR spectrum of gefaryl ester, the product of Example 1;

[0031] Figure 3 The image shows the carbon NMR spectrum of gefaryl ester, the product of Example 1. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0033] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, methods, and instruments used are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0034] The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used in the following embodiments, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0035] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1 to 5” is disclosed, the described range should be interpreted as including ranges “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range. In this specification and claims, range definitions may be combined and / or interchanged, unless otherwise stated, these ranges include all subranges contained therein.

[0036] The indefinite articles “a” and “an” preceding an element or component of this invention do not impose any limitation on the quantity (i.e., number of times) of the element or component. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity clearly refers only to the singular form.

[0037] The specifications and sources of the reagents used in the following examples are shown in Table 1.

[0038] Table 1. Reagent Specifications and Sources

[0039]

[0040]

[0041] The products obtained in the following examples were characterized using 400M NMR (Bruke Aschend 400M NMR). Liquid chromatography-mass spectrometry (LC-MS) conditions: LC-Q-TOF high-resolution mass spectrometry, Bruke Maxis UHRTOF, was used for qualitative and quantitative analysis of the reactants, intermediates, and products in the reaction system. Products were separated by reverse-phase chromatography using a ZORBAX SB-C18 (particle size 1.8μm; 2.1×50mm) at a flow rate of 0.2mL / min, an injection volume of 1μL, a column oven temperature of 40℃, positive ion mode detection, a detection voltage of 1.56kV, a nebulizer (N2) flow rate of 1.5L / min, a drying gas (N2) pressure of 100kPa, an ion collection time of 30ms, a collision energy of 50%, and an MS scan range of 100-600m / z. Quantitative analysis of the samples was performed using the external standard method.

[0042] Example 1: The synthesis method of a gefarin ester in this example is carried out according to the following steps:

[0043] Step 1:

[0044] The following reaction is performed first:

[0045]

[0046] 1075g of β-farnesene as shown in formula (II), 714g of methyl acetoacetate, 5L of ethanol, and 12g of (acetylacetone) dicarbonyl rhodium were added to the reaction vessel. After stirring evenly, the mixture was reacted at 70℃ for 15h. Then, methyl farnesene ketone was obtained by distillation and column chromatography with a purity of 92% and a yield of 89%.

[0047] Then the following reaction occurs:

[0048]

[0049] Add 150g of 1% sodium hydroxide aqueous solution to 1438g of farnesene methyl ester, stir well, heat to 90℃ and react for 4h, cool and separate the layers, neutralize the organic layer with acetic acid to neutral, remove the solvent and volatile components by distillation, and then obtain farnesene acetone as shown in formula (IV) by distillation and column chromatography, with a purity of 90% and a yield of 92%.

[0050] Step 2:

[0051] The following reaction will occur:

[0052]

[0053] 2 L of 10 wt% sodium hydroxide solution and 780 g of elemental iodine were added to 270 g of farnesyl acetone as shown in formula (IV). The mixture was heated to 60 °C and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained. The solution was purified to obtain sodium (4E, 8E, 12E)-5, 9, 13-trimethyltetradecanoate as shown in formula (V), with a purity of 91% and a yield of 81%.

[0054] Step 3:

[0055] The following reaction will occur:

[0056]

[0057] 1 L of methanol solution containing 285 g of sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate (as shown in formula (V)) was added to the reaction vessel. Then, 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid were added. After stirring until homogeneous, the mixture was heated to reflux at 90 °C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefaryl ester with a purity of 95% and a yield of 80%.

[0058] The resulting product, gefa ester 1 H NMR (400MHz, CDCl3) δ5.32m 1H,5.08m 4H,4.57d(J=7.06)2H,2.31d(J=2.56)2H,2.29d(J=2.25)2H,2.05m 12H,1.96dt(J=9.50,5.59)6H,1.68m9H,1.66m 6H.

[0059] The resulting product, gefa ester 13 C NMR (101MHz, CDCl3) δ173.34,141.94,136.54,134.96,131.71,131.15,124.39,124.06,123.77,123.14,118.49, 61.20,39.71,39.53,34.52,31.87,26.75,26.70,26.53,26.30,23.47,23.38,17.64,17.61,16.41,15.96,15.94.

[0060] Example 2: The synthesis method of a gefarin ester in this example is carried out according to the following steps:

[0061] Step 1:

[0062] The following reaction is performed first:

[0063]

[0064] 1075g of α-farnesene as shown in formula (III), 714g of methyl acetoacetate, 5L of ethanol, and 12g of (acetylacetone) dicarbonyl rhodium were added to the reaction vessel. After stirring evenly, the mixture was reacted at 70°C for 15h. Then, methyl farnesene ketone was obtained by distillation and column chromatography with a purity of 87% and a yield of 83%.

[0065] Then the following reaction occurs:

[0066]

[0067] Add 150g of 1% sodium hydroxide aqueous solution to 1438g of farnesene methyl ester, stir well, heat to 90℃ and react for 4h, cool and separate the layers, neutralize the organic layer with acetic acid to neutral, remove the solvent and volatile components by distillation, and then obtain farnesene acetone as shown in formula (IV) by distillation and column chromatography, with a purity of 90% and a yield of 93%.

[0068] Step 2:

[0069] The following reaction will occur:

[0070]

[0071] 2 L of 10 wt% sodium hydroxide solution and 780 g of elemental iodine were added to 270 g of farnesyl acetone as shown in formula (IV). The mixture was heated to 60 °C and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained. The solution was purified to obtain sodium (4E, 8E, 12E)-5, 9, 13-trimethyltetradecanoate as shown in formula (V), with a purity of 87% and a yield of 81%.

[0072] Step 3:

[0073] The following reaction will occur:

[0074]

[0075] 1 L of methanol solution containing 285 g of sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate (as shown in formula (V)) was added to the reaction vessel. Then, 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid were added. After stirring until homogeneous, the mixture was heated to reflux at 90 °C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefaryl ester with a purity of 95% and a yield of 80%.

[0076] Example 3: The synthesis method of a gefarin ester in this example is carried out according to the following steps:

[0077] Step 1:

[0078] The following reaction is performed first:

[0079]

[0080] 1075g of a 1:1 mixture of α-farnesene and β-farnesene as shown in formulas (II)-(III), 714g of methyl acetoacetate, 5L of ethanol, and 12g of (acetylacetone) rhodium dicarbonyl were added to a reaction vessel. After stirring evenly, the mixture was reacted at 70°C for 15h. Then, methyl farnesene ketone was obtained by distillation and column chromatography with a purity of 90% and a yield of 94%.

[0081] Then the following reaction occurs:

[0082]

[0083] Add 150g of 1% sodium hydroxide aqueous solution to 1438g of farnesene methyl ester, stir well, heat to 90℃ and react for 4h, cool and separate the layers, neutralize the organic layer with acetic acid to neutral, remove the solvent and volatile components by distillation, and then obtain farnesene acetone as shown in formula (IV) by distillation and column chromatography, with a purity of 88% and a yield of 87%.

[0084] Step 2:

[0085] The following reaction will occur:

[0086]

[0087] 2 L of 10 wt% sodium hydroxide solution and 780 g of elemental iodine were added to 270 g of farnesyl acetone as shown in formula (IV). The mixture was heated to 60 °C and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained. The solution was purified to obtain sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate as shown in formula (V), with a purity of 89% and a yield of 80%.

[0088] Step 3:

[0089] The following reaction will occur:

[0090]

[0091] 1 L of methanol solution containing 285 g of sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate (as shown in formula (V)) was added to the reaction vessel. Then, 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid were added. After stirring until homogeneous, the mixture was heated to reflux at 90 °C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefaryl ester with a purity of 95% and a yield of 80%.

[0092] Example 4: The synthesis method of a gefarin ester in this example is carried out according to the following steps:

[0093] Step 1:

[0094] First, the in-situ extract fermentation broth fermented by the strain in patent CN111607545A was distilled and concentrated to obtain a concentrate with a farnesene concentration of 75%, which was used as a raw material for the preparation of gefarin.

[0095] Then the following reaction occurs:

[0096]

[0097] 1075g of β-farnesene as shown in formula (II), 714g of methyl acetoacetate, 5L of ethanol, and 12g of (acetylacetone) dicarbonyl rhodium were added to the reaction vessel. After stirring evenly, the mixture was reacted at 70°C for 15h. Then, methyl farnesene ketone was obtained by distillation and column chromatography with a purity of 87% and a yield of 79%.

[0098] Then proceed with the following reaction:

[0099]

[0100] Add 150g of 1% sodium hydroxide aqueous solution to 1438g of farnesene methyl ester, stir well, heat to 90℃ and react for 4h, cool and separate the layers, neutralize the organic layer with acetic acid to neutral, remove the solvent and volatile components by distillation, and then obtain farnesene acetone as shown in formula (IV) by distillation and column chromatography, with a purity of 83% and a yield of 82%.

[0101] Step 2:

[0102] The following reaction will occur:

[0103]

[0104] 1.5 L of 20 wt% sodium hypochlorite solution was added to 270 g of farnesyl acetone as shown in formula (IV), the mixture was heated to 60 °C and stirred for 4 h, cooled and separated, the aqueous layer was retained and purified to obtain sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate as shown in formula (V), with a purity of 80% and a yield of 82%.

[0105] Step 3:

[0106] The following reaction will occur:

[0107]

[0108] 1 L of methanol solution containing 285 g of sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate (as shown in formula (V)) was added to the reaction vessel. Then, 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid were added. After stirring until homogeneous, the mixture was heated to reflux at 90 °C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefaryl ester with a purity of 95% and a yield of 80%.

[0109] The above description is merely a preferred embodiment of the present invention. These specific embodiments are different implementations based on the overall concept of the present invention, and the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing gefaryl esters from farnesene and its derivatives, characterized in that, This method is performed in the following steps: Step 1: First, farnesene and acetoacetate are synthesized into farnesene ketoester under the action of a catalyst, and then decarboxylated by hydrolysis under the action of an alkaline catalyst to obtain farnesene acetone; Step 2: Farnesyl acetone was subjected to a haloform reaction using a halogenating agent to obtain sodium (4E,8E,12E)-5,9,13-trimethyltetradecanoate. Step 3: Under the action of p-toluenesulfonic acid, the product of step 2 is subjected to an esterification reaction using an esterification reagent to obtain gefaryl ester.

2. The method according to claim 1, characterized in that, In step 1, farnesene is one or a mixture of two of β-farnesene and α-farnesene; acetoacetate is selected from methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isobutyl propyl acetoacetate, and tert-butyl acetoacetate; the catalyst is a rhodium-containing compound; and the alkaline catalyst is selected from aqueous solutions of sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, lithium chloride, lithium bromide, and lithium iodide.

3. The method according to claim 2, characterized in that, The rhodium-containing compound is (acetylacetone) dicarbonyl rhodium.

4. The method according to claim 1, characterized in that, In step 1, the mass ratio of farnesene to acetoacetate and catalyst is (70-90):(50-70):1, and the mass ratio of farnesene ketoester to dry weight of alkaline catalyst is (900-1000):

1.

5. The method according to claim 1, characterized in that, In step 2, the halogenating reagent is selected from a mixture of elemental iodine and sodium hydroxide solution, or sodium hypochlorite solution, and the haloform reaction temperature is 20-70℃.

6. The method according to claim 5, characterized in that, When the halogenating reagent is a mixture of elemental iodine and sodium hydroxide solution, the mass ratio of elemental iodine, sodium hydroxide and farnesyl acetone is (2-5):(0.5-2):

1. When the halogenating reagent is sodium hypochlorite solution, the mass ratio of sodium hypochlorite and farnesyl acetone is (0.5-2.5):

1.

7. The method according to claim 1, characterized in that, In step 3, the esterification reagent is 1-bromo-3,7-dimethyl-2,6-octadiene, and the mass ratio of the product, esterification reagent and catalyst in step 2 is (15-25):(10-20):

1. The esterification reaction temperature is 50-140℃.

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